Carvedilol has the systemic name of (±) 1-(9H-carbazol-4-yloxy)-3-[[2(2-methoxyphenoxy)ethyl]amino]-2-propanol, (CAS Registry No. 72956-09-3). As shown in FIG. 1, the structure of carvedilol has a chiral center. Carvedilol is a racemic mixture of R(+) and S(−) enantiomers, where α-adrenergic blocking activity is present in both R(+) and S(−) enantiomers and non-selective β-adrenoreceptor blocking activity is present in the S(−) enantiomer.
Carvedilol is a non-selective β-adrenergic blocking agent used clinically for treating cardiovascular diseases (heart failure and hypertension). Its vasodilator properties are attributed to a1-blocking activity, as is its capacity to inhibit oxidative stress in coronary smooth muscle. Although carvedilol has been tested only in adults, several studies report that it is effective in children with heart failure.
The only currently available oral formulation of carvedilol is in dosage tablet form. COREG® tablets were approved by the FDA on Sep. 14, 1995 for treatment of congestive heart failure and hypertension in adults. Extemporaneous suspensions including carvedilol have been prepared by reconstituting crushed COREG® tablets in deionized water and sorbitol 70% or with ORA-SWEET® oral syrup vehicle and ORA-PLUS®oral suspending vehicle, resulting in carvedilol concentrations of 0.625 and 1.25 mg/ml, respectively. It has been reported that these suspensions have limited stability.
Carvedilol is practically insoluble in water, and hence is routinely compounded in liquid form with limited shelf life for patients who may have trouble swallowing tablets or require specific dose titration. Currently, there is no FDA approved oral carvedilol liquid formulation.
However, some patients, specifically pediatric and geriatric patient populations, may dislike or have difficulty swallowing solid oral dosage forms, which can lead to associated disadvantages, such as patient non-compliance. In such situations, oral liquid dosage forms, including solutions, suspensions and emulsions, can be easier to administer and more suitable for use.
Poor bioavailability of pharmaceuticals presents a major challenge in designing oral dosage forms. The oral bioavailability depends on several factors, including aqueous solubility, drug permeability, dissolution rate, first-pass metabolism, presystemic metabolism, and susceptibility to efflux mechanisms. The most frequent causes of low oral bioavailability are attributed to poor solubility and low permeability. For orally administered drugs, solubility is the most important rate limiting parameter to achieve a desired concentration in systemic circulation for pharmacological response. Accordingly, liquid compositions containing active pharmaceutical ingredients that are completely solubilized in a liquid composition are more advantageous over suspensions. The extent of solubility of a substance in a specific solvent is measured as the saturation concentration, at which the addition of more solute does not increase its concentration in solution. The extent of solubility ranges widely, from infinitely soluble (fully miscible) (for example, ethanol in water) to poorly soluble (for example, silver chloride in water). Solubility is based on the highest-dose strength of an immediate release product. A drug is considered highly soluble when the highest dose strength is soluble in 250 mL or less of aqueous media over the pH range of 1 to 7.5.
Accordingly, there remains a need for a highly bioavailable, highly soluble, stable carvedilol oral solution that can address these problems, while safely and effectively providing proper and consistent administration of carvedilol with accuracy and precision to patients who have difficulty swallowing solid dosage forms.